Signal Transduction Program ? Project Summary/Abstract The Signal Transduction (ST) Program focuses on the molecular signals within and between cells that drive cancer. Members of the Program include experts who bring an in-depth understanding of different families of signaling proteins, integrated with investigators who have a deep knowledge of cancer biology and ability to develop cutting-edge technologies and systems with which to study molecular and cellular functions. As such, the program generates basic discoveries that can drive the development of untapped areas for cancer therapy. The ST Program has two major overarching themes/goals. The first major goal is to identify and target signaling in cancer. Aberrant biochemical cascades stimulate cancer cells; therefore, an in-depth characterization of signal transduction elements is essential for developing potent therapeutics and circumventing drug resistance. Members of the ST Program have taken an integrated approach to the definition and characterization of such signaling elements and their dysregulation in cancer, thereby focusing attention on potential therapeutic targets that are amenable to chemical or biological inhibitors. The second major goal is to characterize and attack tumor-host interactions driving cancer. Tumors contain host cells (such as immune, mesenchymal, and vascular cells) that communicate with cancer cells. Although genomic changes within the cancer cells drive cancer, the interactions with the host cells promote cancer and is mediated by signaling downstream of mitogens, cytokines, extracellular matrix proteins, and cell-cell interacting receptors. Members of the ST Program aim to unravel the interplay between the intracellular signaling pathways and host responses, with a particular focus on mechanisms involved in evasion from the immune system and tumor-host interactions in tumor progression. Instrumental to achieving the overall goals of the program is the development of novel animal and in vitro model systems of cancer. Mouse models, intravital imaging to visualize the cellular activities, and in vitro model systems such as organoids address defined aspects of tumor-host interactions and can be probed with pharmacological and genetic inhibitors to facilitate the identification of novel drivers, modulators, and suppressors of tumor formation and progression. The ST Program has 9 CSHL faculty members. There is much interaction and synergy among them and with other Program members as well as with collaborators at other institutions, other NCI-designated Centers, hospitals, and biotech firms. Support, Shared Resources, and infrastructure from the CCSG as well as institutional funds have been critical to assemble our Program and enable vital future enhancements. As of 8/1/15, ST members held $4.1M of direct costs secured from NCI, other peer reviewed and non-peer reviewed, cancer-related support. Of this, $2.6M was from NCI and other peer reviewed cancer sources. Since 9/1/10, the ST Program published 90 cancer-related articles, 32 (36%) involved multiple CCSG members; 18 (20%) intra-programmatic, and 20 (22%) inter-programmatic; 6 are both intra- and inter-programmatic.